Abstract

We have previously shown that the Histone Deacetylase Inhibitor (HDACi) trichostatin A (TSA) can sensitize cancer cells to UV radiation by facilitating the formation of Cyclobutane pyrimidine dimers (CPD) without increasing the levels of HDAC1. Here we show that HDAC9 and HDAC11 are upregulated in response to UV radiation in a number of human melanoma cell lines. Both HDAC9 and HDAC11 have an hnRNP A18 signature motif in their 3′UTR. hnRNP A18 is a new regulator of protein translation that can confer growth advantages to tumor cells by specifically increasing the stability and translation of mRNA transcripts harboring its signature motif. Our data indicate that HDAC9 and 11 levels correspond to hnRNP A18 level in response to UV radiation in several melanoma cell lines while hnRNP A18 and HDAC 9 and 11 are not upregulated in response to UV radiation in the normal human fibroblasts Malme cells or the normal melanocytes HEMa-LP. Moreover, clonogenic colony survival assays indicate that melanoma cells expressing higher hnRNP A18 endogenous levels are more resistant to UV radiation than cells expressing lower hnRNP A18 levels. In addition, down regulation of hnRNP A18 prevents HDAC 9 and 11 upregulation in response to UV radiation. Furthermore, overexpression of hnRNP A18 increases further the levels of HDAC 9 and 11 in response to UV radiation. These data suggest that upregulation of HDAC9 and 11 in response to hnRNP A18 activation contribute to UV resistance and may increase sensitization to UV-induced cell killing by HDACi.